In monoamine neurons, the potential importance of autoregulation of neuronal activity has received varied attention. For example, although the pharmacological concept of dopamine autoreceptors is slightly more than 10 years old, clinical trials are actively attempting to exploit this important regulatory step of chemical neurotransmission in diseases associated with hyperdopaminergic activity. In contrast, clinical studies utilizing direct, selective pre- or postsynaptic serotonin (5-HT) receptor modulation are relatively rare. On reason for this deficit is the lack of basic, in vivo neuropharmacological studies specifically directed at the question of 5-HT agonist-induced modulation of presynaptic 5-HT function. The objective of the studies proposed herein is a further understanding of autoregulation in central 5-HT neurons and the functional consequences of such mechanisms in rats. Proposed studies to be conducted in vivo are designed to examine the mechanism by which 5-HT agonists attenuate 5-HT synthesis, the role of impulse flow in controlling 5-HT synthesis, and the potential role of nerve-terminal 5-HT autoreceptors modulating transmitter synthesis. Moreover, parallel issues concerning 5-HT synthesis and release will be addressed in vitro using brain slices as a simplified system to study isolated nerve terminals. In addition to further defining the neurobiology of 5-HT autoregulation, these studies are designed to elucidate the functional pharmacology of novel 5-HT agonists such as 8-hydroxy-2-(di-n-propylamino)tetralin (8-OHDPAT). After studies on the mechanism of 5-HT autoregulation are in progress, the longer-term objectives of the proposal concerning changes in autoreceptor responsiveness will be initiated. Specifically, experiments will test the hypothesis that repeated exposure of terminal 5-HT autoreceptors to elevated levels of 5-HT (subsequent to chronic treatment with reuptake blockers) will lead to an alteration in autoreceptor modulation of neuronal activity. Thus, these studies will refine and extend concepts of 1) 5-HT autoregulation, and 2) the possible mechanisms by which chronic antidepressants modify functional presynaptic 5-HT activity.